tbuckley/cabot-search huggingface dataset:
EXTH-54. CO-CULTURE OF PATIENT-DERIVED GLIOBLASTOMA CELL LINES WITH AUTOLOGOUS PBMCS FOR THE INVESTIGATION OF ONCOLYTIC VIRUS RESPONSE
Authors: Eftychia Stavrakaki, Wouter B L van den Bossche, Rutger Balvers, Lisette B Vogelezang, Cristina Teodosio, Dana A M Mustafa, Willem de Koning, Andrew P Stubbs, William F Goins, Hiroshi Nakashima, E Antonio Chiocca, Jacques J M van Dongen, Clemens M F Dirven, Martine L M Lamfers
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The dismal prognosis of glioblastoma (GBM) patients, with a median survival of less than 15 months despite maximal therapy urgently warrants new therapeutic approaches. Clinical trials employing oncolytic viruses (OVs) have shown encouraging results, however, in each OV clinical trial only a small subset of patients responded to treatment. As inter-tumoral heterogeneity has been the key challenge in treating GBM, we hypothesized that development of an in vitro co-culture model for assessment of viral replication and subsequent immune response might ultimately predict in vivo OV efficacy for individual GBM patients. METHODS 20 patient-derived GBM cell cultures were tested with dose-ranges of two clinically relevant OVs (DNX2401 and rQnestin34.5 V1) to determine the EC50 values (half-maximal effective concentration). To discriminate between responders and non-responders six of these cultures were infected using MOI 10 for DNX2401 and 0.25 for rQnestin34.5V1, and co-cultured with autologous PBMCs. OV-induced changes in gene and protein expression of immune associated genes were assessed using targeted gene expression (NanoString Technology) and ELISA. RESULTS DNX2401 EC50 values ranged from 0.35 to &amp;gt; 600 and from 0.04 to 1.77 for rQnestin34.5V1. Induction of pro-inflammatory cytokines and chemokines differed per virus and per patient. Enhanced OV infection or oncolysis efficiency did not lead to increased levels of IFNγ production. Importantly, longer exposure to dexamethasone prior to PBMC isolation correlated with suppressed IFNγ production. CONCLUSION We established an autologous GBM cells/PBMCs co-culture model which reflects inter-tumoral heterogeneity in terms of cytokine induction and virus-specific changes in gene and protein expression upon OV infection. Immune activation is not directly related to degree of infection or oncolysis and can be hampered by prolonged prior dexamethasone use. These first results support our hypothesis that improved prediction of response rates in oncolytic virotherapy for GBM may require a personalized approach with an in vitro test system.
CTNI-37. REPEATED OPENING OF THE BLOOD-BRAIN BARRIER WITH THE SKULL-IMPLANTABLE SONOCLOUD-9 (SC9) DEVICE: PHASE 1 TRIAL OF NAB-PACLITAXEL AND SC9 IN RECURRENT GLIOBLASTOMA
Authors: Adam M Sonabend, Andrew Gould, Yu Luan, Ye Hou, Mikoto A Kobayashi, Brandyn Castro, Daniel Y Zhang, Li Chen, Farida Korobova, Christina Amidei, Mark Youngblood, John Patrick F Bebawy, Benjamin Liu, Craig Horbinski, Carole Desseaux, Irene B Helenowski, Hui Zhang, Miguel Muzzio, Feng Yue, Michael Canney, Roger Stupp
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The blood-brain barrier (BBB) is a major impediment to pharmacological treatment of gliomas. Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU/MB), temporarily opens the BBB. Here we investigate the pharmacokinetics and safety of this approach of repeated delivery of albumin-bound paclitaxel (Abraxane®, ABX) to the peri-tumoral brain. To perform LIPU/MB-based BBB opening prior to ABX infusions, we used a novel 6 x 6 cm device with 9 ultrasound emitters (SC9) that is implanted in a skull window after tumor resection. METHODS A Phase 1 dose-escalation trial using Bayesian adaptive design was conducted (NCT04528680). Patients with recurrent operable glioblastoma, a WHO PS ≤ 2 and adequate bone marrow and organ function were eligible. After tumor resection and implantation of SC9, repeated cycles of BBB opening by LIPU/MB immediately followed by ABX, was performed every 3 weeks. Intraoperative LIPU/MB and low dose ABX was given prior to tumor resection allowed for investigation tissue concentrations and pharmacokinetics. RESULTS Seventeen patients have been treated at six escalating ABX dose levels (40-260 mg/m2). At dose of 260 mg/m2, a grade 3 reversible taxane-associated dose limiting encephalopathy was observed in one patient. The patient continued treatment at a lower dose in subsequent cycles. A second patient exhibited encephalopathy on cycle 2. One patient developed grade 2 cumulative peripheral neuropathy. Intraoperative pharmacokinetic studies showed that ABX tissue concentrations in non-enhancing peri-tumoral brain were increased 3.7-fold after LIPU/MB. sc-RNA-sequencing showed transcriptional dysregulation of membrane transporters, pathways related to trans-cytosis as well as cell-cell and cell-matrix adhesion. CONCLUSIONS The LIPU/MB using skull-implantable ultrasound enhances the penetration of ABX in large regions of the brain. The procedure can be performed repeatedly and safely. LIPU-based BBB opening leads to transcriptional alterations in brain endothelium. Funding: NIH/NCI 1R01CA245969-01A1, CarThera (SC9 devices), BMS/Celgene (Abraxane®).
NIMG-88. A TRANSFER LEARNING APPROACH FOR AUTOMATIC SEGMENTATION OF TUMOR SUB-COMPARTMENTS IN PEDIATRIC MEDULLOBLASTOMA USING MULTIPARAMETRIC MRI: PRELIMINARY FINDINGS
Authors: Rohan Bareja, Marwa Ismail, Douglas Martin, Ameya Nayate, Benita Tamrazi, Ralph Salloum, Ashley Margol, Alexander Judkins, Sukanya Iyer, Peter de Blank, Pallavi Tiwari
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Superior outcomes for medulloblastoma (MB) requires precise surgical resection which can be guided by tumor segmentation. We present the first attempt at automatic segmentation of MB tumors via a hierarchical transfer-learning model that (1) segments the entire tumor habitat (enhancing tumor (ET), necrosis/non-enhancing tumor (NET), edema), followed by (2) training separate models for each of the sub-compartments. Transfer learning from adult brain tumors is used to optimize segmentation of tumor sub-compartments for pediatric MB. METHODS We evaluated 300 adult glioma studies (BRATS) and 49 pediatric MB studies (2-18 years old), both consisting of Gd-T1w, T2w, FLAIR sequences. The MB cohort was collected from Children's Hospital of Los Angeles (Nf19) and Cincinnati Children’s Hospital Medical Center (Nf30). Scans were registered to age-specific pediatric atlases, followed by bias correction and skull-stripping. Ground truth for the tumor sub-compartments was generated via consensus across two experts. We employed a 3D nn-Unet segmentation model on BRATS dataset using initial learning rate of 0.01, stochastic gradient descent as optimizer, and an average of dice loss and cross-entropy loss as the loss function. A hierarchical transfer learning model with Models Genesis was then applied, which allowed for fine tuning every layer on the pediatric MB dataset, across 5-fold cross validation. Dice score was used as performance metric, such that a perfect overlap between ground truth and prediction would yield a Dice score of 1. RESULTS Our 3D hierarchical segmentation model yielded mean dice scores of 0.85±0.03 for the entire tumor habitat; 0.77±0.048 for ET, 0.73±0.09 for edema, and 0.56±0.09 for NET + necrosis segmentation, across cross-validation runs. Overall, tumor outline and segmentation matched well with the ground truth, especially for the entire tumor, ET and enhancing tumor sub-compartments. CONCLUSIONS Our segmentation approach holds promise for accurate automated delineation of the tumor sub-compartments in pediatric Medulloblastoma.
CTNI-25. REGORAFENIB IN RECURRENT GLIOBLASTOMA PATIENTS: A MULTICENTRIC REAL-LIFE STUDY
Authors: Francesco Bruno, Alessia Pellerino, Edoardo Pronello, Rosa Palmiero, Valentina Polo, Roberta Vitaliani, Elena Trincia, Valeria Internò, Camillo Porta, Riccardo Soffietti, Roberta Rudà
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND In the phase 2 REGOMA trial, regorafenib improved overall survival, as compared to lomustine, for glioblastoma (GBM) patients at first progression after chemoradiation. Here, we present the results of a real-life multicentre study that analysed response to treatments, tolerability, and outcome of GBM patients treated with regorafenib at first tumour progression. PATIENTS AND METHODS Regorafenib was given following an escalation dose protocol (1st cycle: 80 mg/day for 2 weeks, then 120 mg/day for one week; 2nd cycle: 120 mg/day for 2 weeks, then 160 mg/day for one week; 160 mg/day from the 3rd cycle). Progression-free survival (PFS) and overall survival (OS) were defined as time from regorafenib initiation and disease progression or death. RESULTS From January 2020 to January 2022, 66 GBM patients were included. Median age was 60.0 years. MGMTp methylation was found in 30 patients (45.5%). Median dose was 120 mg/day 21q28 day, which was lower than that used in REGOMA trial (149 mg). Median PFS (mPFS) was 2.7 months and median OS (mOS) 7.1 months. RANO response to regorafenib was partial response (PR) in 10 (15.1%), stable disease in 14 (21.2%), and progressive disease in 42 (63.7%) patients. Forty-six (69.7%) patients presented adverse events of any grade, and 21 (31.8%) grade III-IV toxicity. Two patients only (3.0%) interrupted regorafenib due to toxicity. In a multivariable analysis, factors associated with disease progression were higher age (p = 0.035) and absence of MGMTp methylation (p = 0.024). CONCLUSION In our study, mPFS and mOS were similar to those of the 59 patients enrolled in the regorafenib arm of REGOMA trial (2.7 vs 2.0 months; 7.1 vs 7.4 months, respectively). However, we observed a higher rate of PRs (15% versus 3.0%). Moreover, we had a lower incidence of discontinuations due to toxicity, maybe because of the lower dose intensity.
CTNI-63. A STUDY OF NIRAPARIB COMBINED WITH RADIOTHERAPY IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Wei Jiang, Zheng Wang
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND There is no standard therapy for recurrent glioblastoma (rGBM), which has a poor survival, from 3 to 10 months. Radiotherapy is an available option for patients with rGBM, and it could invoke DNA damage, thus leading to tumor cell death. Niraparib is a poly(ADP-ribose) polymerase inhibitor. Preclinical data showed that Niraparib enhances the radiosensitivity of glioblastoma cells. Thus we hypothesize that radiotherapy synergizes with Niraparib to improve the clinical efficacy of anti-tumor.Method:We conducted a phase 2 study combining Niraparib, radiotherapy, and maintenance Niraparib in 30 patients with rGBM. Niraparib(300mg QD) was started at cycle 1 of radiotherapy (55Gy total) and continued until progression or unacceptable toxicity The primary endpoint was 6 month PFS. Secondary endpoints included toxicity, QoL, and OS Result：As of 4/31/2022, 14 patients with a median age of 47 years old (range 26-69) were enrolled. 64.29% were female. Eight patients（57.1%）had experienced ≥ 2 previous therapy（range 1-4）. The MGMT methylation status was available for 12 patients, and 9（64.3%）had unmethylated MGMT. The median follow-up was 167 days (95%CI 124-263). PFS 6 was 36% (95%CI 12.17%-60.92%), OS 6 was 82.61%(95%CI 46.51%-95.34%). The mPFS was 157 days (95%CI 93-188), the mOS was not reached (95%CI 188-NA), three patients had an OS of more than 10 months by the data submitted. The ORR was 35.7%, one patient achieved CR,four achieved PR. Niraparib combined radiotherapy showed efficacy in controlling local lesions. At 1 and 3 months, local control rate was 85.7% and 64.3% ,respectively. The most common serious adverse event was thrombocytopenia（28.57%）which could be controlled by adjusting the dosage of Niraparib. CONCLUSION Niraparib combined radiotherapy is well tolerated and shows efficacy in rGBM patients. Survival data will be updated.Clinical registration number: NCT04715620
BIOM-59. NOVEL BIOMARKER DISCOVERY AND DIAGNOSTICS FOR INTRA-AXIAL BRAIN TUMORS, USING CSF PROTEOMICS
Authors: Alireza Mansouri, Nicholas Mikolajewicz, Shahbaz Khan, Mara Trifoi, Brad Zacharia, Michael Glantz, Gelareh Zadeh, Thomas Kislinger
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Invasive brain sampling is typically necessary for reliable diagnosis and prognostication of intra-axial brain tumors but carries risk of morbidity. Liquid biopsy of proximal fluids may mitigate this risk. Through direct contact with the tumor microenvironment and, as an ultra-filtrate of plasma, the cerebrospinal fluid may be the ideal matrix. Reflecting the tumor phenotype, proteomic analyses are critical. Here we identified diagnostic CSF proteomic signatures and putatively novel biomarkers for glioblastoma (GBM), brain metastases (BM), and central nervous system lymphoma (CNSL). METHODS CSF samples were retrospectively retrieved from the Penn State Neuroscience Biorepository and profiled using shotgun proteomics and the MStern approach. Proteomic signatures were identified using machine learning classifiers and survival analyses. RESULTS With as little as 30 µL of CSF, 755 unique proteins were recovered across 73 samples (22 GBM, 17 BM, 14 CNSL, 20 NPH). Proteomic-based classifiers identified malignancy with area under the receiver operating characteristic (AUROC) of 0.94 and distinguished between tumor entities with AUROC ≥0.95. More clinically relevant triplex classifiers, comprised of just 3 proteins, distinguished between tumor entities with AUROC of 0.75-0.89. Novel biomarkers were identified, including GAP43, TFF3 and CACNA2D2, and characterized using single-cell RNA sequencing. DISCUSSION Reliable classification of intra-axial malignancies using low CSF volumes is feasible, allowing for longitudinal tumor surveillance. Based on emerging evidence, upfront implantation of CSF reservoirs in brain tumor patients warrants consideration.
NIMG-27. THE PROGNOSTIC VALUE OF FET PET IN PATIENTS WITH RECURRENT GLIOMA TREATED WITH BEVACIZUMAB
Authors: Jan-Michael Werner, Myriam Winkels, Philipp Lohmann, Garry Ceccon, Michael Wollring, Caroline Tscherpel, Elena Bauer, Roland Goldbrunner, Gabriele Stoffels, Karl-Josef Langen, Gereon R Fink, Norbert Galldiks
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND After multiple recurrences in glioma patients, bevacizumab is frequently used as salvage therapy. In this group of patients, we evaluated the prognostic value of amino acid PET using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) before initiation of bevacizumab. METHODS We retrospectively identified adult glioma patients at recurrence with (i) at least one or more previous recurrences, (ii) who were treated with bevacizumab, and (iii) who underwent FET PET imaging before bevacizumab initiation. Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean), metabolic tumor volume (MTV), and dynamic parameters (i.e., time-to-peak, slope) were obtained from FET PET. Additionally, contrast-enhancing volumes on MRI were calculated. Threshold values of imaging parameters for evaluating the prognosis were established by ROC analyses using overall survival (OS) of ≥ 6 months as reference. The prognostic value of imaging parameters was subsequently evaluated using the log-rank test and multiple logistic regression analyses. RESULTS Twenty-eight patients (glioblastoma, 96%) with a median of 2 recurrences (range, 1-5) were eligible for data evaluation. The patients received a median number of 7 bevacizumab cycles (range, 1-27). The static FET PET parameter TBRmean was the best parameter (threshold, 2.1; AUC, 0.78; P=0.014) to identify patients with a significantly longer OS (8.2 vs. 4.9 months; P=0.044). In contrast, the MTV, contrast-enhancing volume, and dynamic FET PET parameters were not significant. TBRmean remained significant in multiple logistic regression analysis (P=0.031), indicating an independent predictor for OS. CONCLUSION Our data suggest that static FET PET allows identifying patients with longer OS before initiation of bevacizumab.
NCMP-09. IMPACT OF TUMOUR CHARACTERISTICS AND CANCER TREATMENT ON CEREBROVASCULAR MORTALITY AFTER GLIOMA DIAGNOSIS: EVIDENCE FROM A POPULATION-BASED CANCER REGISTRY
Authors: Paul Brennan, Kai Jin, Jonine Figueroa, Cathie Sudlow
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Brain tumour patients have the highest stroke mortality rates among cancer types, but the factors associated with fatal stroke remain unknown. We aimed to examine to what extent brain tumour grade, a marker of biological aggressiveness, tumour size and cancer treatment are associated with cerebrovascular mortality among patients with malignant glioma, the most common and aggressive brain tumour. METHODS We conducted a retrospective, observational cohort study using the US National Cancer Institute’s state and regional population-based cancer registries (NCI SEER). We identified adult patients with a diagnosis of malignant glioma (2000 to 2018, Nf72,916). The primary outcome of interest was death from cerebrovascular disease. Cox regression modelling estimated the associations with cerebrovascular mortality of tumour grade, tumour size and treatment (surgery, radiotherapy, chemotherapy), calculating hazard ratios (HR) adjusted for these factors as well as for age, sex, race, marital status and calendar year. RESULTS Higher grade (Grade IV vs Grade II: HR=2.47, 95% CI=1.69-3.61, p&amp;lt; 0.001) and larger brain tumours (size 3 to &amp;lt; 6 cm: HR=1.40, 95% CI=1.03 -1.89, p&amp;lt; 0.05; size ≥ 6 cm: HR=1.47, 95% CI=1.02-2.13, p&amp;lt; 0.05 compared to size &amp;lt; 3cm) were associated with increased cerebrovascular mortality. Having cancer treatment was associated with decreased risk (surgery: HR= 0.60, p&amp;lt; 0.001; chemotherapy: HR=0.42, p&amp;lt; 0.001; radiation: HR= 0.69, p&amp;lt; 0.05). However, among patents surviving five years or more from their cancer diagnosis radiotherapy was associated with higher risk of cerebrovascular mortality (HR 2.73, 95% CI 1.49-4.99, p&amp;lt; 0.01). CONCLUSIONS More aggressive tumour characteristics are associated with increased cerebrovascular mortality, and treatment was associated with lower risk within 5 years of diagnosis. Radiotherapy increased risk of fatal cerebrovascular outcome five-years after cancer diagnosis. Further research is needed to better understand the long-term cardiovascular consequences of radiation therapy, and whether the consequent risk can be mitigated.
QLTI-20. DIGITAL SOLUTIONS TO IMPROVE DATA QUALITY IN NEUROONCOLOGY RESEARCH
Authors: Amit Ray, Arka Sanka, Kiran Prathapa, Vijay Sreegiriraju, K V R N Kiran Kumar, Yadagiri Balagoni, Samyuktha Sunkara, Ravi Teja Sunkara, Sharath Chandra Nandoori, Sarath Vuyyuru, Pankaj Mishra, Surya Prakash Madiraju
Journal: Neuro-Oncology (2022)

Abstract PROBLEM Data quality impacts the validity of results obtained through clinical research due to several reasons. These include degradation of tumor tissue and other biological samples while being transported across large distances. Other concerns related to data collection include breach in patient privacy and loss and corruption of data. Such issues lead to generation of results that are either unreliable or unsuitable for analysis. Blockchain based digital solutions for clinical trials may be an answer to the problem. SOLUTION In this abstract we review one such software ‘Elsy’ that we have used to collect around 1000 samples from more than 70 centres nationwide. Elsy had been deployed on the smartphone and desktop and used by clinical trial teams to plan, execute and monitor the trial across multiple geographical locations. Collection of tumor specimens was monitored from the time the specimens left the operating room by leveraging blockchain technologies. Patient data was imported into the system seamlessly by integration with hospital electronic medical records systems. Customised data forms were mapped to automatically import data fields that were relevant. Once recruited, all patient sensitive data was immediately obfuscated, and a bar code was assigned to the patient, which served as the unique patient identifier. Data was encrypted in transit and at rest on a cloud server, with access requiring 2-factor authentication. Data viewing and editing permissions were tailored to meet patient privacy and security requirements. Changes in data were logged and monitored, eliminating wilful or accidental manipulation of data. AI and ML tools were integrated with the system to perform advanced analysis. CONCLUSION Digital platforms may have the potential to revolutionise the clinical trials systems by enabling the collection of clean and secure data.
IMMU-43. CXCR3 SIGNALING ENGAGES GLIOMA INFILTRATING T CELLS AND IS REQUIRED FOR THE ANTITUMOR EFFICACY OF INNATE STIMULATING IMMUNOTHERAPY
Authors: Michael Brown, Yuanfan Yang, Zachary Mckay, Darell Bigner, David Ashley, Matthias Gromeier, Smita Nair
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND T cell dysfunction is well documented in patients with gliomas, yet mechanisms explaining T cell dysfunction in gliomas are lacking. Recent evidence links CXCR3 signaling and functional immune surveillance in both preclinical models and human data sets. METHODS Bulk and single cell RNA-seq data sets were used to compare CXCR3 ligand expression in gliomas to that of other solid tumor types. The role of CXCR3 signaling in mediating the recruitment and phenotype of tumor infiltrating lymphocytes (TILs) was tested using CXCR3 blockade and genetic deletion of CXCR3 in murine tumor models. The capacity of relevant innate stimulating immunotherapies to induce CXCR3 ligands in human glioma tissue was assessed using an ex vivo glioma slice culture assay, and the contribution of CXCR3 signaling to polio virotherapy (PVSRIPO) and STING agonist therapy was tested in murine models. RESULTS Relative to other solid tumors, gliomas express significantly lower levels of CXCR3 ligands (CXCL9, 10, and 11), which are largely expressed by tumor associated myeloid cells. Blocking CXCR3 signaling profoundly restricted TIL recruitment in murine gliomas, and resulted in decreased TIL stemness features coinciding with exacerbated exhaustion phenotypes. Polio virotherapy and STING agonism efficiently induced CXCR3 ligand production in fresh human glioma tissue in a manner dependent upon myeloid cells, and at levels similar to that induced by the same agents in melanoma and breast cancer tissue. CXCR3+ TILs expressed higher levels of memory and activation markers, proliferated more, and were required for the antitumor efficacy of both polio virotherapy and a STING agonist in mice. CONCLUSION This work indicates that CXCR3 signaling, a key contributor to cancer immune surveillance, is disrupted in human gliomas relative to other solid tumor types. Intratumor virotherapy and STING agonists hold potential to rectify diminished CXCR3 ligand expression in gliomas.